The present invention relates generally to pharmaceutical compounds and methods for the treatment of disorders relating to the nervous system in animals and humans. More specifically, the invention relates to the use of a subset of gamma-pyrones in pharmaceutically acceptable forms for the treatment of various disorders relating to the peripheral and central nervous system. For the purposes of this description, the terms “disorders relating to the nervous system” or “neurotic disorders” include among others such conditions as pain, depression, anxiety, insomnia, neurosis, etc., as well as pain and other symptoms associated with the abstinence syndrome experienced by chemical and drug abuse patients. All of these conditions involve the neurons of the nervous system.
Sedative compounds known in the art are a chemically varied group of compositions of natural and synthetic origin that predominantly have a tranquilizing effect on the central nervous system. Different sedatives produce different physiological effects. Understanding of these effects is helpful in selectively treating various disorders. This mechanism of action is not always entirely clear but it is believed that sedative drugs in general are intended to cause selective suppression of subcortical (limbus) and cortical brain structures, which regulate emotions.
The mildest examples of sedative drugs include extracts of motherwort, passiflora, valerian root (Tinctura Valeriana), bromides of caustic metals (Kalium bromatum, Natrium bromatum). These drugs typically cause only a light tranquilizing effect on the subject. Stronger tranquilizers are used to lower a patient's anxiety. These are synthetic medicinal preparations, examples of which include derivatives of benzodiazepin (diazepam), diphenyl methane (benactyzine), propanediol (mepropan) and trioxazin.
Hypnotic compounds (Phenobarbital for example) in small doses are also used as sedative drugs along with various neuroleptic agents (aminazine, tisercin) and some other compounds. Examples of such additional compounds include Bekhterev's mixture (sodium bromide, lychnis infusion, codeine phosphate), Corvalolum (ethyl ether of α-bromine isovaleric acid, monosodium salt of Phenobarbital, mint oil, ethyl alcohol, water), and Validol (menthol solution in menthyl valerate).
An example of a general sedative compound is shown in the U.S. Pat. No. 5,506,268 by Balandrin describing the use of isovaleramide as a mild anxiolytic and sedative agent.
The side effects of these medicinal preparations are a reduced ability to concentrate, drowsiness, and lower mental and physical effectiveness. In addition, patients often become dependent on a sedative in the course of treatment, reducing the desired effect, and a replacement sedative is needed to maintain the desired effect.
The need therefore exists for new sedative compounds that do not cause these side effects or drug dependency.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. In considering approaches to the treatment of pain, it is important to understand the distinction between acute and persistent or chronic pain. Acute pain occurs as a result of tissue injury, and is mediated by chemical, mechanical or thermal stimulation of pain receptors known as nociceptors. Acute pain serves a protective function, conditioning avoidance behavior of situations and events leading to such potential tissue damage.
In contrast to acute pain, chronic or persistent pain in itself constitutes a disease which serves no protective biological function. Chronic pain is unrelenting and can persist for years and frequently cannot be associated with a single or specific injury. Chronic pain predominantly constitutes chronic inflammatory pain (e.g. arthritis) or “neuropathic pain”, which can be defined as pain initiated or caused by a primary lesion or dysfunction within the nervous system (Mersky and Bogduk, Classifications of Chronic Pain, 2nd edition. Seattle IASP Press: 394, 1994, De Andres and Garcia-Ribas, Pain Practice 3: 1-7, 2003). Neuropathic pain is associated with a variety of disease states and present in clinical settings for patients with a wide range of symptoms. (Woolf and Mannion Lancet 353: 1959-64, 1999). It does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron Clinical J. Pain 16 (suppl2):512-520, 2003).
Neuropathic pain is often reported as having a lancinating or continuous burning character and is frequently associated with the appearance of abnormal sensory signs such as allodynia and hyperalgesia. Alloydnia is defined as pain resulting from a stimulus that does not normally elicit a painful response, and hyperalgesia is characterized by an increased pain response to normally non-painful stimuli. Some disorders characterized by neuropathic pain include mono-radiculopathies, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, complex regional pain syndromes, back pain and the various peripheral neuropathies. Neuropathic pain may also be associated with diabetes, multiple sclerosis, radio- or chemotherapy and infections such as HIV and tuberculosis. Neuropathic pain may also result as a side effect of drug treatment or abuse.
For clinical purposes, nociceptive pain can be classified as somatic or visceral. Somatic pain results from prolonged activation of nociceptive receptors in somatic tissues such as a bone, joint, muscle or skin. Visceral pain, on the other hand, manifests from activation of nociceptive receptors by pathological mechanisms such as mechanical injury, x-ray irradiation, toxic agents, etc.
Neuropathic pain can be characterized by the following clinical features (Teng and Mekhail, Pain Practice, 3: 8-12, 2003, Rajbhandari et al, Pain, 83: 627-629, 1999, Melzack et al, Ann NY Acad Sci, 933: 157-174, 2001):                1. There is the presence of an abnormal, unpleasant sensation (dysesthesia) that frequently has a burning or electrical quality with an occasional paroxysmal, brief, shooting, or stabbing quality;        2. Although the onset of most neuropathic pain is within days after the precipitating injury, there is no absolute temporal relationship to the originating neural trauma such that it can begin weeks, months, or even years later;        3. Pain may be felt in a region of sensory deficit;        4. Non-noxious stimuli may be painful (allodynia);        5. Noxious stimuli may produce greater than normal response (hyperalgesia);        6. There may be an increase in the intensity of pain with repeated stimuli and the pain may persist after the removal of stimuli.        
Although there are numerous available therapies for acute pain caused by stimulation of the nociceptors, especially treatment with opioid and non-steroidal anti-inflammatory drugs (NSAIDs), neuropathic pain is an area of largely unmet therapeutic need. Due to the distinct patho-physiochemical mechanisms and clinical manifestations associated with neuropathic pain relative to pain caused as a result of nociceptor stimulation or acute pain, agents useful in the treatment of pain caused as a result of nociceptor stimulation or acute pain have reduced effectiveness in neuropathic pain treatment.
There are basically two kinds of analgesics: non-narcotics and narcotics. It should be noted that some references include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) in the class of analgesics, because they have some analgesic properties. Aspirin and NSAIDS primarily have an anti-inflammatory effect, as opposed to being solely analgesic.
Acetaminophen (a NSAIDS) is the most commonly used over-the-counter, non-narcotic analgesic. Acetaminophen is a popular pain-reliever because it is both effective for mild to moderate pain relief and relatively inexpensive. It must be emphasized though that the safety of acetaminophen is tied to proper use of the drug (use according to specific prescribing instructions). If acetaminophen is not used according to the directions on the label, serious side effects and possible fatal consequences can occur. For example, taking more than 4000 mg/day, or using it long-term, can increase the risk of liver damage. The risk of liver damage with acetaminophen use is also increased by ingesting alcohol. Many people do not realize that acetaminophen is found in more than 600 over-the-counter drugs. It can be found in combination with other active ingredients in many cold, sinus, and cough medications. The cumulative effect of acetaminophen must be considered if one is taking multiple drugs which contain acetaminophen. In the body, acetaminophen changes into metabolites which are eliminated from the body, and by taking more than the recommended maximum daily dose of acetaminophen, more toxic metabolites are produced than can be eliminated, resulting in liver damage.
There are two types of narcotic analgesics: opiates and opioids (derivatives of opiates). Opiates are the alkaloids found in opium (a white liquid extract of unripe seeds of the poppy plant). Opioids are any medications which bind to opioid receptors in the central nervous system or gastrointestinal tract. There are four broad classes of opiates/opioids:                1. Endogenous opioid peptides (produced in the body: endorphins, dynorphins, enkephalins);        2. Opium alkaloids (such as morphine, codeine, thebaine);        3. Semi-synthetic opioids (such as heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine); and        4. Fully synthetic opioids (such as pethidine or Demerol, methadone, fentanyl, propoxyphene, pentazocine, buprenorphine, butorphanol, tramadol, and more).        
Opiates and opioids are used in medicine as strong analgesics, for relief of severe or chronic pain. Interestingly, there is no upper limit for the dosage of opiates and opioids used to achieve pain relief, but the dose must be increased gradually to allow for the development of tolerance to adverse effects (for example, respiratory depression). According to eMedicine, “Some people with intense pain get such high doses that the same dose would be fatal if taken by someone who was not suffering from pain.”
There have been debates over the addictive potential of opiates and opioids vs. the benefit of their analgesic properties for treating non-malignant chronic pain, such as chronic arthritis. Some experts believe opiates and opioids can be taken safely for years with minimal risk of addiction or toxic side effects. The enhanced quality of life which opiates and opioids may provide the patient must be considered. Common side effects of opiates and opioids are nausea, vomiting, drowsiness, dry mouth, miosis (contraction of the pupil), orthostatic hypotension (blood pressure lowers upon sudden standing), urinary retention and constipation. Less common side effects noted are confusion, delirium, hallucinations, hives, itch, hypothermia, bradycardia (slow heart rate), tachycardia (rapid heart rate), raised intracranial pressure, uretic or bilary spasms, muscle rigidity and flushing. The most severe side effects are respiratory depression and a fatal overdose.
In particular, the effectiveness of opiates and opioids in the treatment of neuropathic pain is diminished relative to their use in the treatment of pain caused as a result of nociceptor stimulation or acute pain, and drug dose response curves for treatment of neuropathic pain are shifted to the right of those for treatment of pain caused as a result of nociceptor stimulation or acute pain (Teng and Mekhail, 2003 supra, De Andres and Garcia-Ribas, 2003 supra, Stuteet al J. Pain Symptom Management 25: 1123-1131, 2003).
As reported by Salynn Boyles in WebMD Medical News on Mar. 26, 2003 in an article entitled, Morphine-Like Drug Cuts Neuropathic Pain, but Risks Still Unknown, researchers found that high-dose treatment with opioids provided much greater chronic pain relief than lower doses of the drug. Pain was reduced by 36% among patients in the high-dose group, compared with 21% in those taking lower doses. “When you have pain you aren't looking for a 20% or 30% drop in that pain,” the McGill University professor told WebMD. “The objective is to have no pain, and very few patients experience complete pain relief with the available treatments.”
Due to the diminishing effects over time (tolerance) of opioids in subjects suffering from neuropathic pain, the use of opioids is often frequent and sustained. This over use is often associated with addiction, the development of tolerance and an increase in the number and severity of side effects associated with opioid use.
A pharmacological mainstay of the conventional clinical management of neuropathic pain are tricyclic anti-depressants and certain anti-convulsants, but even these achieve a reduction in pain of less than 50% in greater than 50% of patients treated. These agents are also associated with significant side effect profiles.
There is a pressing need therefore for improved regimes for the treatment of neuropathic and inflammatory pain as well as improved regimes for treating disease conditions which have a neuropathic or inflammatory pain component.
Pharmaceutical compounds used in treating patients with chemical and drug abuse define an important sub-category in the general area of drugs. It is common knowledge that there are many individuals who become addicted to certain types of drugs taken either for medical reasons or for “recreational”, non-medical use. Addiction, as has been defined by the Drug Addiction Committee of the National Research Council, is a state of periodic or chronic intoxication detrimental to the individual and produced by the repeated administration of a drug. Thus, an “addictive drug” as used herein is one that is initially used for any one of a number of purposes, e.g., for the relief of physical or psychic pain, and which if used consistently leads to dependency on the part of the individual taking the drug. The addicted individual develops a continuing craving (physical and psychological) for the drug and experiences “withdrawal symptoms” if an attempt is made to discontinue drug use. The terms “withdrawal syndrome” and “abstinence syndrome” are used to mean the same condition of the patient for the purposes of this description.
Various pharmacological approaches for treating drug dependence have been tried. These approaches have typically involved attempts at treating the physical craving for the abused drug or alleviating the physical symptoms associated withdrawal. The following references relate to some known methods and compositions for treating drug addiction and/or symptoms of withdrawal from drug dependency. U.S. Pat. No. 4,786,653 by Golwyn relates to the administration of phenelzine or an equivalent phenylalkylhydrazine, substances that are physiologically incompatible with addictive drugs such as amphetamines and cocaine. U.S. Pat. Nos. 1,796,977 and 1,782,111 describe the preparation of disulfuram (“Antabuse”), an alcohol deterrent. U.S. Pat. No. 4,696,818 by Kim relates to a method for alleviating symptoms associated with a variety of drugs, the method comprising administering an herbal composition to the drug dependent individual. U.S. Pat. No. 3,706,831 by Plotnikoff also describes a method for treating addiction to any one of a number of different types of drugs, which method involves administering to the addict a composition containing 2-imino-5-phenyl-4-oxazolidinone. U.S. Pat. Nos. 4,117,161 and 4,124,715 by Pozuelo disclose methods and compositions for treating withdrawal from narcotics and amphetamines which involve administration of alphamethyl-para-tyrosine or fusaric acid to the affected individual.
Treatment of nicotine withdrawal is described in the U.S. Pat. No. 4,325,952 by Baiocchi et al. and involves the use of a piperazine compound to treat the symptoms associated withdrawal from nicotine. U.S. Pat. No. 4,788,189 by Glazer involves treatment of nicotine withdrawal by administration of clonidine in conjunction with a tricyclic antidepressant drug. U.S. Pat. No. 4,276,890 by Fichera describes a composition for alleviating symptoms of nicotine withdrawal by administering to the affected individual a composition containing a gamma-pyrone such as maltol or ethyl maltol.
Opiates and their numerous forms, including opium, codeine, morphine, heroin, etc. as well as its other alkaloids and including synthetic or derived substitutes, constitute a large segment of narcotics in general. Their use has become more widespread recently, in both the “recreational drug” and pharmaceutical segments. The primary method of treatment for dependence on narcotics is the discontinuation of narcotics and minimization of the abstinence syndrome. Officially permitted methods of the discontinuation of narcotics involve the replacement of the offending drug from the opioid receptors and their substitution by one of three possible types of ligands:                1. Antagonists of opioid receptors such as naltrexone, naloxone, nalmephine, and antaxone;        2. Agonists/antagonists such as pentazocine, butorphanol, nalbuphine, and buprenorphine aimed to activate receptors of a particular subtype such as kappa, while blocking receptors of another subtype such as mu; and        3. Agonists such as methadone and others that are better controlled and have a lower affinity to receptors, this method is called substitution therapy.        
Each of these approaches has its own disadvantages. In the case of antagonists, there is no relief from the pain and other symptoms of withdrawal syndrome. The most severe, long-lasting manifestations of withdrawal syndrome cannot be eliminated either by initial general narcosis or with the assistance of anesthetics, tranquilizers, neuroleptics or antidepressants. These substances have numerous side effects while the incidence of relapse is rather high. With the use of agonists, the withdrawal syndrome is less pronounced; however, a dependence often develops on the medication that is also, in fact, a narcotic, although with a lower affinity to opioid receptors than, for instance, morphine or heroin. Besides, the duration of such substitution therapy is rather long, up to 3-6 months and more. Due to their psychological instability, drug addicts often “change their mind” and refuse treatment.
Therefore, a very substantial need exists for a therapeutic method of treating drug abuse such that a drug-addicted individual is readily able to discontinue use of an abused drug without encountering the above-mentioned problems and withdrawal symptoms.